ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.71G>C (p.Arg24Pro) (rs104894097)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167312 SCV000218160 pathogenic Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing The p.R24P pathogenic mutation (also known as c.71G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 71. The arginine at codon 24 is replaced by proline, an amino acid with dissimilar properties. This alteration has been detected in numerous familial melanoma kindreds with and without pancreatic cancer; in three such families, the alteration co-segregated with disease in 21 out of 23 affected individuals overall (Soufir N et al. Hum. Mol. Genet. 1998 Feb;7(2):209-16; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87; MaKie RM et al. J. Invest. Dermatol. 1998 Aug;111(2):269-72; Newton Bishop JA et al. Br. J. Cancer 1999 Apr;80(1-2):295-300; Holland EA et al. Genes Chromosomes Cancer 1999 Aug; 25(4):339-48; Della Torre G et al. Br. J. Cancer 2001 Sep;85(6):836-44). Functional studies have shown that p.R24P mutants have varying levels of decreased binding affinity to CDK4 while other assays measuring cell cycle arrest and oxidative regulation have demonstrated activity comparable to wild type (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; McKenzie HA et al. Hum. Mutat. 2010 Jun;31(6):692-701; Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133(4):1043-51; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87, Becker TM et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; Jones R et al. Cancer Res. 2007 Oct;67(19):9134-41). Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000167312 SCV000266063 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000236320 SCV000292535 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted CDKN2A c.71G>C at the cDNA level, p.Arg24Pro (R24P) at the protein level, and results in the change of an Arginine to a Proline (CGG>CCG). This variant has been reported in multiple individuals with hereditary melanoma, and has been shown to segregate with disease in large families (Holland 1995, Harland 1997, MacKie 1998, Monzon 1998, Holland 1999, Della Torre 2001, Bishop 2002, Begg 2005, Nikolaou 2011, Burgstaller-Muehlbacher 2015). This variant has also been reported in individuals with pancreatic cancer (McWilliams 2011, Zhen 2015). Functional studies of the variant suggest it is abnormal, impairing binding to CDK4, not properly inhibiting growth, and altering cellular localization (Monzon 1998, Becker 2001, McKenzie 2010). CDKN2A Arg24Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDKN2A Arg24Pro is located in the 1st ANK repeat (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available evidence, we consider CDKN2A Arg24Pro to be pathogenic.
Counsyl RCV000410204 SCV000488917 likely pathogenic Melanoma-pancreatic cancer syndrome 2016-07-19 criteria provided, single submitter clinical testing
Invitae RCV000472219 SCV000545544 pathogenic Hereditary melanoma 2020-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 24 of the CDKN2A (p16INK4a) protein (p.Arg24Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs104894097, ExAC 0.005%). This variant has been reported in individuals with multiple primary melanomas and shown to segregate with disease in multiple families (PMID: 8570179, 9699728, 15146471, 16905682, 18363633, 21801156, 10390011, 26225579, 17047042, 17047042, 26225579). This variant has also been reported in individuals with pancreatic cancer (PMID: 21150883, 15146471, 16905682, 25356972). ClinVar contains an entry for this variant (Variation ID: 9415). Experimental studies have shown that this missense change disrupts p16INK4a protein function, including cellular localization, CDK4 binding, and normal growth suppression (PMID: 20340136, 23190892, 11595726, 18843795, 15945100). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000167312 SCV000684536 pathogenic Hereditary cancer-predisposing syndrome 2020-03-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763193 SCV000893806 pathogenic Melanoma-pancreatic cancer syndrome; Cutaneous malignant melanoma 2; Melanoma and neural system tumor syndrome 2018-10-31 criteria provided, single submitter clinical testing
Department of Pediatrics,Memorial Sloan Kettering Cancer Center RCV000410204 SCV001478114 pathogenic Melanoma-pancreatic cancer syndrome 2020-12-15 criteria provided, single submitter research
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000410204 SCV001499642 pathogenic Melanoma-pancreatic cancer syndrome 2020-04-02 criteria provided, single submitter clinical testing
OMIM RCV000010022 SCV000030243 risk factor Cutaneous malignant melanoma 2 1998-08-01 no assertion criteria provided literature only

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